PROJECT SUMMARY/ABSTRACT Worldwide, the quality of life of over half a million surviving head-and-neck cancer patients per year is drastically decreased due to co-irradiation of healthy saliva-secreting salivary glands. Current therapies to rescue hypo-salivation only provide temporary relief; hence new therapies for permanent tissue repair are needed. In a mouse model, we induced successful repair of irradiated salivary glands by transplanting KIT+ stem/progenitor cells. However, this population of stem/progenitor cells decreases with age and is heterogeneous; hence, currently compromising our ability to efficiently use these cells for therapy. Recent discoveries in our lab have shown that transcription factor SOX10 tightly regulates proliferation and differentiation in fetal KIT+ cells. In this proposal we hypothesize that only a subpopulation of adult KIT+ cells, which express SOX10, retain stem cell self-renewal capacity. Thus, we aim to: (1) characterize the multipotent stem cells within the KIT+ cell population, (2) define the role of transcription factor SOX10 in maintaining adult KIT+ cells, and (3) characterize the molecular heterogeneity and SOX10 signature in human KIT+ cells. Overall, the scientific ideas proposed here will expand our knowledge of salivary gland stem cell populations, and will significantly improve future hypo-salivation rescuing by stem cell-based therapies.